Substituted cyclohexylcarboxylic acid amide compounds

ABSTRACT

Substituted cyclohexylcarboxylic acid amide compounds, processes for their production, pharmaceutical compositions containing these compounds and the use of substituted cyclohexylcarboxylic acid compounds for producing pharmaceutical compositions for treating conditions or disease states associated with the opioid receptor system and/or with noradrenalin and/or serotonin re-uptake.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of international application no.PCT/EP2005/004908, filed May 6, 2005 designating the United States ofAmerica and published in German on Nov. 24, 2005 as WO 2005/110977, theentire disclosure of which is incorporated herein by reference. Priorityis claimed based on Federal Republic of Germany patent application no.DE 10 2004 023 632.1, filed May 10, 2004.

BACKGROUND OF THE INVENTION

The present invention relates to substituted cyclohexylcarboxylic acidamide compounds, to processes for their production, to pharmaceuticalcompositions containing these compounds and to the use ofcyclohexylcarboxylic acid compounds for producing pharmaceuticalcompositions.

The treatment of chronic and non-chronic pain conditions has greatimportance in medicine. There is a worldwide need for effective methodsof treating pain. The urgent need for action for patient-oriented andpurposeful treatment of chronic and non-chronic pain conditions, thisbeing taken to mean the successful and satisfactory treatment of painfor the patient, is documented in the large number of scientific paperswhich have recently appeared in the field of applied analgesics andfundamental research work on nociception.

Conventional μ-opioids such as morphine are very effective in thetreatment of strong to very strong pain and are of great importance forthe treatment of pain. However, it may be advantageous if, in additionto the μ-opioid receptor, other opioid receptors, in particular the ORL1receptor, are affected since the pure μ-opioids also exhibit undesiredside effects such as obstipation and respiratory depression, but mayalso lead to dependency. The opioid receptors δ, κ and ORL1 are alsoinvolved in the occurrence of pain (Opioids: Introduction, pp. 127-150,Further Opioid Receptors, 455-476 in: Analgesics—From Chemistry andPharmacology to Clinical Application, Wiley VCH, 2002).

It is also known that influencing of serotonin and/or noradrenalinre-uptake can be beneficial to the effects and side effects of opioids(Example: Tramadol, cf. Opioids with Clinical Relevance: Tramadol,228-230 in: Analgesics—From Chemistry and Pharmacology to ClinicalApplication, Wiley VCH, 2002).

The ORL1 receptor is also involved in the regulation of furtherphysiological and pathophysiological processes. These include inter alialearning and memory formation (Manabe et al., Nature, 394, 1997, pp.577-581), Hörvermögen [Hearing capacity] (Nishi et al., EMBO J., 16,1997, pp. 1858-1864) and numerous further processes. In a synopsis byCalo et al. (Br. J. Pharmacol. 129, 2000-1261) there is an overview ofthe indications or biological procedures, in which the ORL1 receptorplays a part or could highly probably play a part. Mentioned inter aliaare: analgesia, stimulation and regulation of nutrient absorption,effect on μ-agonists such as morphine, treatment of withdrawal symptoms,reduction of the addiction potential of opioids, anxiolysis, modulationof motor activity, memory disturbances, epilepsy; modulation ofneurotransmitter release, in particular of glutamate, serotonin anddopamine, and therefore neurodegenerative diseases; affecting thecardiovascular system, triggering an erection, diuresis,anti-natriuresis, electrolyte balance, arterial blood pressure,water-retention diseases, intestinal motility (diarrhoea), relaxation ofthe respiratory tract, micturation reflex (urinary incontinence). Theuse of agonists and antagonists as anoretics, analgesics (also whenadministered with opioids) or nootropics will also be discussed.

Structurally related compounds are known from the prior art (WO02090317) which have an affinity with the ORL1 receptor. An effect onnoradrenalin and serotonin re-uptake has not previously been describedfor this structural class.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide new pharmaceuticallyactive compounds which act on the opioid receptor system.

Another object of the invention is to provide pharmaceuticalcompositions for treatment or inhibition of various conditions ordisease states associated with the opioid receptor system.

A further object of the invention is to provide a process for producingsuch compounds.

An additional object of the invention is to provide a method of treatingor inhibiting various conditions or disease states known to beassociated with the opioid receptor system.

It is also an object of the invention to provide compounds whichinfluence noradrenalin and serotonin re-uptake.

The invention therefore relates to substituted cyclohexylcarboxylic acidamide derivatives of general formula I,

wherein

-   -   R¹ and R² independently of one another represent H; CHO;        respectively saturated or unsaturated, branched or unbranched,        singly or multiply substituted or unsubstituted C₁₋₅ alkyl;        respectively saturated or unsaturated, singly or multiply        substituted or unsubstituted C₃₋₈ cycloalkyl; or respectively        singly or multiply substituted or unsubstituted aryl, C₃₋₈        cycloalkyl or heteroaryl bound by C₁₋₃ alkyl; or    -   R¹ and R² together represent CH₂CH₂O CH₂CH₂, CH₂CH₂NR¹⁰CH₂CH₂ or        (CH₂)₃₋₆, wherein R¹⁰ represents H; respectively saturated or        unsaturated, branched or unbranched, singly or multiply        substituted or unsubstituted C₁₋₅ alkyl; respectively saturated        or unsaturated, singly or multiply substituted or unsubstituted        C₃₋₈ cycloalkyl; respectively singly or multiply substituted        aryl or heteroaryl; or respectively singly or multiply        substituted or unsubstituted aryl, C₃₋₈ cycloalkyl or heteroaryl        bound by C₁₋₃ alkyl;    -   R³ represents respectively saturated or unsaturated, branched or        unbranched, singly or multiply substituted or unsubstituted C₁₋₅        alkyl; respectively saturated or unsaturated, singly or multiply        substituted or unsubstituted C₃₋₈ cycloalkyl; respectively        unsubstituted or singly or multiply substituted aryl, heteroaryl        or C₃₋₈ cycloalkyl bound by a C₁₋₃ alkyl group; respectively        unsubstituted or singly or multiply substituted naphthyl,        anthracenyl, thiophenyl, benzothiophenyl, furyl, benzofuranyl,        benzodioxolanyl, indolyl, indanyl, benzodioxanyl, pyrrolyl,        pyridyl, pyrimidyl or pyrazinyl; phenyl, 2-fluorophenyl,        3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 4-chlorophenyl,        3-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl,        2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-methylphenyl,        3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl,        3-methoxyphenyl, 4-methoxyphenyl, 2-trifluoromethylphenyl,        3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-ethylphenyl,        3-ethylphenyl, 4-ethylphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl,        4-ethoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl,        4-hydroxyphenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl,        3,5-dichlorophenyl, 2,4-dichlorophenyl, 2,3-difluorophenyl,        3,4-difluorophenyl, 3,5-difluorophenyl, 2,4-difluorophenyl,        2-fluoro-3-chlorophenyl, 2-chloro-3-fluorophenyl,        2-chloro-4-fluorophenyl, 2-fluoro-4-chlorophenyl,        4-fluoro-3-chlorophenyl, 4-fluoro-3-methylphenyl,        4-tert.-butylphenyl, 4-fluoro-3-chlorophenyl,        4-bromo-3-fluorophenyl, 3,5-bis(trifluoromethyl)phenyl,        4-chloro-2-trifluoromethylphenyl, 2-methoxy-5-methylphenyl,        5-chloro-2-methoxyphenyl, 4-phenoxyphenyl, 2-methylthiophenyl,        3-methylthiophenyl, 4-methylthiophenyl,        5-fluoro-2-methoxyphenyl, 4-chloro-3-trifluoromethyl or        4-bromo-2-methylphenyl;    -   R⁴ represents —(CR⁶R⁷)_(n)R⁸, wherein        -   n represents 0, 1, 2, 3, 4, 5 or 6        -   R⁶ represents H or saturated or unsaturated, branched or            unbranched, unsubstituted or singly or multiply substituted            C₁₋₅ alkyl,        -   R⁷ represents H, saturated or unsaturated, branched or            unbranched, unsubstituted or singly or multiply substituted            C₁₋₅ alkyl, or COOR⁹, wherein R⁹ represents H or saturated            or unsaturated, branched or unbranched, unsubstituted or            singly or multiply substituted C₁₋₅ alkyl; or        -   R⁶ and R⁷ form a ring (CH₂)_(k)CHR⁸(CH₂)_(m), where k=1, 2            or 3 and m=1 or 2; and        -   R⁸ represents respectively unsubstituted or singly or            multiply substituted cycloalkyl, aryl or heteroaryl;    -   R⁵ represents H or —(CH₂)₁R⁸, wherein 1 represents 1, 2 or 3, or    -   R⁴ and R⁵ together represent CH₂CH₂OCH₂CH₂ or CH₂CH₂NR¹¹CH₂CH₂,        wherein R¹¹ represents H; respectively saturated or unsaturated,        branched or unbranched, singly or multiply substituted or        unsubstituted C₁₋₅ alkyl; respectively saturated or unsaturated,        singly or multiply substituted or unsubstituted C₃₋₈ cycloalkyl;        respectively singly or multiply substituted or unsubstituted        aryl or heteroaryl; or respectively singly or multiply        substituted or unsubstituted aryl, C₃₋₈ cycloalkyl or heteroaryl        bound by C₁₋₃ alkyl;        -   in the form of the racemate; the enantiomers, diastereomers,            mixtures of the enantiomers or diastereomers or an            individual enantiomer or diastereomer; the bases and/or            salts of physiologically acceptable acids or cations.

The compounds according to the invention exhibit good binding to theμ-receptor and to the ORL1 receptor but also to other opioid receptors.Surprisingly it has been found that the compounds are also goodinhibitors of noradrenalin and serotonin re-uptake. They are thereforealso capable of treating depression and/or bulimia and/or anorexiaand/or catalepsy and/or anxiolysis and/or increasing alertness and/orlibido.

The terms “C₁₋₅ alkyl” and “C₁₋₃ alkyl”, according to this invention,include acyclic saturated or unsaturated hydrocarbon radicals, which maybe branched or straight chained and unsubstituted or singly or multiplysubstituted, with 1, 2, 3, 4 or 5 C atoms or 1, 2 or 3 C atoms, i.e.C₁₋₅ alkanyls, C₂₋₅ alkenyls and C₂₋₅ alkynyls or C₁₋₃ alkanyls, C₂₋₃alkenyls and C₂₋₃ alkynyls. Alkenyls have at least one C—C double bondand alkynyls at least one C—C treble bond. Alkyl is advantageouslyselected from the group comprising methyl, ethyl, n-propyl, 2-propyl,n-butyl, iso-butyl, sec.-butyl, tert.-butyl, n-pentyl, iso-pentyl,neo-pentyl, n-hexyl, 2-hexyl; ethylenyl (vinyl), ethynyl, propenyl(—CH₂CH═CH₂, —CH═CH—CH₃, —C(=CH₂)—CH₃), propynyl (—CH—C≡CH, —C≡C—CH₃),1,1-dimethylethyl, 1,1-dimethylpropyl, butenyl, butinyl, pentenyl andpentynyl.

For the purposes of this invention the term “cycloalkyl” or “C₃₋₈cycloalkyl” denotes cyclic hydrocarbons with 3, 4, 5, 6, 7 or 8 carbonatoms, wherein the hydrocarbons may be saturated or unsaturated (but notaromatic), unsubstituted or singly or multiply substituted. With respectto cycloalkyl, the term also comprises saturated or unsaturated (but notaromatic) cycloalkyls, in which one or two carbon atoms are replaced bya heteroatom, S, N or O. C₃₋₈ cycloalkyl is advantageously selected fromthe group comprising cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl andcyclooctenyl, but also tetrahydropyranyl, dioxanyl, dioxolanyl,morpholinyl, piperidinyl, piperazinyl, pyrazolinonyl and pyrrolidinyl.

The term “(CH₂)₃₋₆” denotes —CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—CH₂—,—CH₂—CH₂—CH₂—CH₂—CH₂— and CH₂—CH₂—CH₂—CH₂—CH₂—CH₂.

The term “aryl”, according to this invention, denotes carbocyclic ringsystems comprising at least one aromatic ring, but without heteroatomsin only one of the rings, inter alia phenyls, naphthyls andphenanthrenyls, fluoranthenyls, fluorenyls, indanyls and tetralinyls.The aryl radicals can also be condensed with further saturated,(partially) unsaturated or aromatic ring systems. Each aryl radical canbe unsubstituted or singly or multiply substituted, the arylsubstituents being the same or different and in any desired or possibleposition of the aryl. Phenyl or naphthyl radicals are particularlyadvantageous.

The term “heteroaryl” represents a 5-, 6- or 7-membered cyclic aromaticradical, which contains at least 1, optionally also 1, 2, 3, 4 or 5heteroatoms, wherein the heteroatoms may be the same or different andthe heterocycle may be unsubstituted or singly or multiply substituted;in the case of substitution on the heterocycle, the substituents may bethe same or different and in any desired or possible position of theheteroaryl. The heterocycle may also be part of a bi- or polycyclicsystem. Preferred heteroatoms are nitrogen, oxygen and sulphur. It ispreferred for the heteroaryl radical to be selected from the groupcomprising pyrrolyl, indolyl, furyl (furanyl), benzofuranyl, thienyl(thiophenyl), benzothienyl, benzothiadiazolyl, benzothiazolyl,benzotriazolyl, benzodioxolanyl, benzodioxanyl, phthalazinyl, pyrazolyl,imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyridazinyl,pyrimidinyl, pyrazinyl, pyranyl, indazolyl, purinyl, indolizinyl,quinolinyl, isoquinolinyl, quinazolinyl, carbazolyl, phenazinyl,phenothiazinyl or oxadiazolyl, wherein the binding with the compounds ofgeneral structure I can be made via any desired and possible ring memberof the heteroaryl radical.

In conjunction with “alkyl”, the term “substituted”, according to thisinvention, denotes substitution of one or more hydrogen radicals by F,Cl, Br, I, —CN, ═O, NH₂, NH-alkyl, NH-aryl, NH-heteroaryl,NH-cycloalkyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-alkyl-OH,N(alkyl)₂, N(alkyl-aryl)₂, N(alkyl-heteroaryl)₂, N(cycloalkyl)₂,N(alkyl-OH)₂, NO₂, SH, S-alkyl, S-aryl, S-heteroaryl, S-alkyl-aryl,S-alkyl-heteroaryl, S-cycloalkyl, S-alkyl-OH, S-alkyl-SH, OH, O-alkyl,O-aryl, O-heteroaryl, O-alkyl-aryl, O-alkyl-heteroaryl, O-cycloalkyl,O-alkyl-OH, CHO, C(═O)C₁₋₆-alkyl, C(═S)C₁₋₆-alkyl, C(═O)aryl, C(═S)aryl,C(═O)C₁₋₆-alkyl-aryl, C(═S)C₁₋₆-alkyl-aryl, C(═O)-heteroaryl,C(═S)-heteroaryl, C(═O)-cycloalkyl, C(═S)-cycloalkyl, CO₂H, CO₂-alkyl,CO₂-alkyl-aryl, C(═O)NH₂, C(═O)NH-alkyl, C(═O)NH-aryl,C(═O)NH-cycloalkyl, C(═O)N(alkyl)₂, C(═O)N(alkyl-aryl)₂,C(═O)N(alkyl-heteroaryl)₂, C(═O)N(cycloalkyl)₂, SO-alkyl, SO₂-alkyl,SO₂NH₂, SO₃H, PO(O—C₁₋₆-alkyl)₂, Si(C₁₋₆-alkyl)₃, Si(C₃₋₈-cycloalkyl)₃,Si(CH₂—C₃₋₈-cycloalkyl)₃, Si(phenyl)₃,-cycloalkyl, aryl or heteroaryl,wherein multiply substituted radicals are taken to mean those which areeither multiply, for example doubly or trebly, substituted on differentatoms or the same atoms, for example trebly on the same carbon atom, asin the case of CF₃ or —CH₂CF₃ or at different positions, as in the caseof —CH(OH)—CH═CHCHCl₂. Multiple substitution can take place with thesame substituent or with different substituents. A substituent mayoptionally also be substituted for its part; thus —O-alkyl also includesinter alia —O—CH₂—CH₂—O—CH₂—CH₂—OH.

With respect to “aryl”, “heteroaryl” and “cycloalkyl”, according to thisinvention, “singly or multiply substituted” denotes the single ormultiple, for example double, treble, quadruple or quintuple,substitution of one or more hydrogen atoms of the ring system by F, Cl,Br, I, CN, NH₂, NH-alkyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl,NH-alkyl-heteroaryl, NH-cycloalkyl, NH-alkyl-OH, N(alkyl)₂,N(alkyl-aryl)₂, N(alkyl-heteroaryl)₂, N(cycloalkyl)₂, N(alkyl-OH)₂, NO₂,SH, S-alkyl, S-cycloalkyl, S-aryl, S-heteroaryl, S-alkyl-aryl,S-alkyl-heteroaryl, S-cycloalkyl, S-alkyl-OH, S-alkyl-SH, OH, O-alkyl,O-cycloalkyl, O-aryl, O-heteroaryl, O-alkyl-aryl, O-alkyl-heteroaryl,O-cycloalkyl, O-alkyl-OH, CHO, C(═O)C₁₋₆-alkyl, C(═S)C₁₋₆-alkyl,C(═O)aryl, C(═S)aryl, C(═O)-C₁₋₆-alkyl-aryl, C(═S)C₁₋₆-alkyl-aryl,C(═O)-heteroaryl, C(═S)-heteroaryl, C(═O)-cycloalkyl, C(═S)-cycloalkyl,CO₂H, CO₂-alkyl, CO₂-alkyl-aryl, C(═O)NH₂, C(═O)NH-alkyl, C(═O)NH-aryl,C(═O)NH-cycloalkyl, C(═O)N(alkyl)₂, C(═O)N(alkyl-aryl)₂,C(═O)N(alkyl-heteroaryl)₂, C(═O)N(cycloalkyl)₂, S(O)-alkyl, S(O)-aryl,SO₂-alkyl, SO₂-aryl, SO₂NH₂, SO₃H, CF₃, ═O, ═S; alkyl, cycloalkyl, aryland/or heteroaryl; on one atom or optionally on different atoms (whereina substituent can, in turn, optionally be substituted). Multiplesubstitution takes place here using the same or different substituents.

The term “salt” denotes any form of the active ingredient according tothe invention in which it assumes or is charged with an ionic form andis coupled to a counter ion (a cation or anion) or is in solution. Thisalso includes complexes of the active ingredient with other moleculesand ions, in particular complexes complexed by ionic interactions. Inparticular this denotes (and this is also a preferred embodiment of thisinvention) physiologically acceptable salts, in particularphysiologically acceptable salts with cations or bases andphysiologically acceptable salts with anions or acids or even a saltformed with a physiologically acceptable acid or physiologicallyacceptable cation.

The term “physiologically acceptable salt with anions or acids”,according to this invention denotes salts of at least one of thecompounds according to the invention—usually protonated, for example onnitrogen—as a cation with at least one anion which are physiologicallyacceptable—in particular when applied to humans and/or mammals.According to this invention this denotes, in particular, the salt formedwith a physiologically acceptable acid, namely salts of the respectiveactive ingredient with inorganic or organic acids which arephysiologically acceptable—in particular when applied to humans and/ormammals. Examples of physiologically acceptable salts of certain acidsinclude salts of: hydrochloric acid, hydrobromic acid, sulphuric acid,methane sulphonic acid, formic acid, acetic acid, oxalic acid, succinicacid, malic acid, tartaric acid, mandelic acid, fumaric acid, lacticacid, citric acid, glutamic acid, saccharic acid, monomethyl sebacicacid, 5-oxo-proline, hexane-1-sulphonic acid, nicotinic acid, 2-, 3- or4-amino benzoic acid, 2,4,6-trimethyl-benzoic acid, α-lipoic acid,acetyl glycine, phosphoric acid, maleic acid, malonic acid, hippuricacid and/or aspartic acid. The hydrochloride salt, the citrate and thehemicitrate are particularly preferred.

The term “salt formed with a physiologically acceptable acid”, accordingto this invention, denotes salts of the respective active ingredientwith inorganic or organic acids which are physiologically acceptable—inparticular when applied to humans and/or mammals. The hydrochloride andthe citrate are particularly preferred. Examples of physiologicallyacceptable acids include: hydrochloric acid, hydrobromic acid, sulphuricacid, methane sulphonic acid, formic acid, acetic acid, oxalic acid,succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid,lactic acid, citric acid, glutamic acid, saccharic acid, monomethylsebacic acid, 5-oxo-proline, hexane-1-sulphonic acid, nicotinic acid,2-, 3- or 4-amino benzoic acid, 2,4,6-trimethyl-benzoic acid, α-lipoicacid, acetyl glycine, O-acetylsalicylic acid, hippuric acid and/oraspartic acid.

The term “physiologically acceptable salt with cations or bases”,according to this invention, denotes salts of at least one of thecompounds according to the invention—usually a (deprotonated) acid—as ananion with at least one, preferably inorganic, cation, which arephysiologically acceptable, in particular when applied to humans and/ormammals. The salts of the alkali and alkaline-earth metals areparticularly preferred, but also ammonium salts, in particular however(mono) or (di) sodium, (mono) or (di) potassium, magnesium or calciumsalts.

The term “salt formed with a physiologically acceptable cation”,according to this invention denotes salts of at least one of therespective compounds as an anion with at least one inorganic cation,which are physiologically acceptable, in particular when applied tohumans and/or mammals. The salts of the alkali and alkaline-earth metalsare particularly preferred, but also ammonium salts, in particularhowever (mono) or (di) sodium, (mono) or (di) potassium, magnesium orcalcium salts.

In a preferred embodiment of the substituted cyclohexylcarboxylic acidderivatives according to the invention R¹ and R² independently of oneanother represent H; saturated or unsaturated, branched or unbranched,singly or multiply substituted or unsubstituted C₁₋₅ alkyl; or R¹ and R²together form a ring and represent CH₂CH₂OCH₂CH₂, CH₂CH₂NR¹⁰CH₂CH₂ or(CH₂)₃₋₆, wherein R¹⁰ represents H; saturated or unsaturated, branchedor unbranched, singly or multiply substituted or unsubstituted C₁₋₅alkyl. Particularly preferred are substituted cyclohexylcarboxylic acidderivatives, wherein R¹ and R² independently of one another representCH₃ or H, but R¹ and R² do not simultaneously represent H.

Also preferred are substituted cyclohexylcarboxylic acid derivatives,wherein R³ represents respectively unsubstituted or singly or multiplysubstituted cyclopentyl, cyclohexyl, naphthyl, thiophenyl,benzothiophenyl, furyl, benzofuranyl, benzodioxolanyl, indolyl, indanyl,benzodioxanyl or pyridyl; respectively unsubstituted or singly ormultiply substituted C₅₋₆ cycloalkyl, phenyl, naphthyl, anthracenyl,thiophenyl, benzothiophenyl, pyridyl, furyl, benzofuranyl,benzodioxolanyl, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyrimidyl orpyrazinyl bound by a saturated, unbranched C₁₋₂ alkyl group; phenyl,2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl,4-chlorophenyl, 3-chlorophenyl, 2-bromophenyl, 3-bromophenyl,4-bromophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl,2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl,3-methoxyphenyl, 4-methoxyphenyl, 2-trifluoromethylphenyl,3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-ethylphenyl,3-ethylphenyl, 4-ethylphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl,4-ethoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl,2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl,2,4-dichlorophenyl, 2,3-difluorophenyl, 3,4-difluorophenyl,3,5-difluorophenyl, 2,4-difluorophenyl, 2-fluoro-3-chlorophenyl,2-chloro-3-fluorophenyl, 2-chloro-4-fluorophenyl,2-fluoro-4-chlorophenyl, 4-fluoro-3-chlorophenyl,4-fluoro-3-methylphenyl, 4-tert.-butylphenyl, 4-fluoro-3-chlorophenyl,4-bromo-3-fluorophenyl, 3,5-bis(trifluoromethyl)phenyl,4-chloro-2-trifluoromethylphenyl, 2-methoxy-5-methylphenyl,5-chloro-2-methoxyphenyl, 4-phenoxyphenyl, 2-methylthiophenyl,3-methylthiophenyl, 4-methylthiophenyl, 5-fluoro-2-methoxyphenyl,4-chloro-3-trifluoromethyl or 4-bromo-2-methylphenyl.

Particularly preferred are compounds in which R³ represents respectivelyunsubstituted or singly or multiply substituted naphthyl, thiophenyl orpyridyl; respectively unsubstituted or singly or multiply substitutedC₅₋₆ cycloalkyl, phenyl, naphthyl, thiophenyl or pyridyl bound by asaturated, unbranched C₁₋₂ alkyl group; phenyl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 4-chlorophenyl,3-chlorophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl,2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl,3-methoxyphenyl, 4-methoxyphenyl, 2-trifluoromethylphenyl,3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-ethylphenyl,3-ethylphenyl, 4-ethylphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl,4-ethoxyphenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl,3,5-dichlorophenyl, 2,4-dichlorophenyl, 2,3-difluorophenyl,3,4-difluorophenyl, 3,5-difluorophenyl, 2,4-difluorophenyl,2-fluoro-3-chlorophenyl, 2-chloro-3-fluorophenyl,2-chloro-4-fluorophenyl, 2-fluoro-4-chlorophenyl,4-fluoro-3-chlorophenyl, 4-fluoro-3-methylphenyl, 4-tert.-butylphenyl,4-fluoro-3-chlorophenyl, 3,5-bis(trifluoromethyl)phenyl,4-chloro-2-trifluoromethylphenyl, 2-methoxy-5-methylphenyl,5-chloro-2-methoxyphenyl, 4-phenoxyphenyl, 2-methylthiophenyl,3-methylthiophenyl, 4-methylthiophenyl or 4-chloro-3-trifluoromethyl.

Especially particularly preferred are substituted cyclohexylcarboxylicacid derivatives, wherein R³ represents substituted or unsubstitutedpyridyl, or phenyl, 2-fluorophenyl, 3-fluorophenyl or 4-fluorophenyl, inparticular phenyl.

Also preferred are substituted cyclohexylcarboxylic acid derivatives,wherein R⁶ represents H and R⁷ represents H or COOR⁹.

Also preferred are substituted cyclohexylcarboxylic acid derivatives,wherein R⁵ represents H.

Also preferred are substituted cyclohexylcarboxylic acid derivatives,wherein R⁸ represents respectively unsubstituted or singly or multiplysubstituted cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl,benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl,carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl orpyrimidyl, fluorenyl, fluoranthenyl, benzothiazolyl, benzotriazolyl orbenzo[1,2,5]thiazolyl or 1,2-dihydroacenaphtenyl, pyridinyl, furanyl,benzofuranyl, pyrazolinonyl, oxopyrazolinonyl, dioxolanyl, adamantyl,pyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl or quinazolinyl.

Particularly preferred are compounds in which R⁸ represents respectivelyunsubstituted or singly or multiply substituted cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl,benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl,carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl orpyrimidyl.

Especially particularly preferred are substituted cyclohexylcarboxylicacid derivatives, wherein R⁸ represents respectively singly or multiplysubstituted phenyl or indolyl.

Most preferred are substituted cyclohexylcarboxylic acid derivativesselected from the group consisting of:

-   2-[(4-dimethylamino-4-phenyl-cyclohexanecarbonyl)    -amino]-3-(1H-indol-3-yl)-propionic acid methylester-hydrochloride;    non-polar diastereomer;-   2-[(4-dimethylamino-4-phenyl-cyclohexanecarbonyl)    -amino]-3-(1H-indol-3-yl)-propionic acid methylester-hydrochloride;    polar diastereomer;-   4-dimethylamino-4-phenyl-cyclohexanecarboxylic acid    (3-phenyl-propyl)amide hydrochloride; non-polar diastereomer; and-   4-dimethylamino-4-phenyl-cyclohexanecarboxylic acid    (3-phenyl-propyl)amide hydrochloride; polar diastereomer,    in the form of the racemate; the enantiomers, diastereomers,    mixtures of the enantiomers or diastereomers or an individual    enantiomer or diastereomer; the bases and/or salts of    physiologically acceptable acids or cations.

The substances according to the invention act, for example, on the ORL1receptor that is relevant in connection with various diseases, so theyare suitable as a pharmaceutical active ingredient in a pharmaceuticalcomposition. The invention therefore also relates to pharmaceuticalcompositions containing at least one substituted cyclohexylcarboxylicacid derivative according to the invention, and optionally suitableadditives and/or auxiliaries and/or optionally further activeingredients.

The pharmaceutical compositions according to the invention optionallycontain, in addition to at least one substituted cyclohexylcarboxylicacid derivative according to the invention, suitable additives and/orauxiliary agents, therefore also excipients, fillers, solvents,diluents, dyes and/or binders and can be administered as liquidpharmaceutical compositions in the form of injection solutions, drops orjuices, as semi-solid pharmaceutical compositions in the form ofgranules, tablets, pellets, patches, capsules, plasters or aerosols. Thechoice of auxiliary agents, etc. and the quantities thereof to be useddepend on whether the pharmaceutical composition is to be appliedorally, perorally, parenterally, intravenously, intraperitoneally,intradermally, intramuscularly, intranasally, buccally, rectally ortopically, for example to the skin, the mucous membranes or the eyes.Preparations in the form of tablets, dragees, capsules, granules, drops,juices and syrups are suitable for oral application, solutions,suspensions, easily reconstitutable dry preparations and sprays aresuitable for parenteral, topical and inhalative applications.Substituted cyclohexylcarboxylic acid derivatives according to theinvention in a deposit, in dissolved form or in a plaster, optionallywith the addition of agents to promote skin penetration, are suitablepercutaneous application preparations. Orally or percutaneouslyapplicable preparation forms can release the substitutedcyclohexylcarboxylic acid derivatives according to the invention after adelay. The substituted cyclohexylcarboxylic acid derivatives accordingto the invention can also be applied in the form of parenterallong-acting repositories such as implants or implanted pumps. Inprinciple, further active ingredients known to the person skilled in theart can be added to the pharmaceutical compositions according to theinvention.

The quantity of active ingredient to be administered to the patientvaries as a function of the weight of the patient, the method ofapplication, the indication and the severity of the illness.Conventionally, 0.00005 to 50 mg/kg, preferably 0.01 to 5 mg/kg of atleast one substituted cyclohexylcarboxylic acid derivative according tothe invention are applied.

For all of the above-mentioned forms of the pharmaceutical compositionsaccording to the invention, it is particularly preferred if, in additionto at least one substituted cyclohexylcarboxylic acid derivative, thepharmaceutical composition contains a further active ingredient, inparticular an opioid, preferably a strong opioid, in particularmorphine, or an anaesthetic, preferably hexobarbital or halothane.

In a preferred form of the pharmaceutical composition, a containedsubstituted cyclohexylcarboxylic acid derivative is in the form of apure diastereomer and/or enantiomer, as a racemate or as a non-equimolaror equimolar blend of the diastereomers and/or enantiomers.

Both the ORL1 receptor and the further opioid receptors have beenidentified in particular in the occurrence of pain. Accordingly,substituted cyclohexylcarboxylic acid derivatives according to theinvention can be used for producing a pharmaceutical composition for thetreatment of pain, in particular acute, neuropathic or chronic pain.

The invention therefore also relates to the use of a substitutedcyclohexylcarboxylic acid derivative according to the invention forproducing a pharmaceutical composition for treating pain, in particularacute, visceral, neuropathic or chronic pain.

The invention also relates to the use of a substitutedcyclohexylcarboxylic acid derivative according to the invention for thetreatment of anxiety, stress and stress-related syndromes, depression,catalepsy, epilepsy, Alzheimer's disease, senile dementia, generalcognitive dysfunction, learning and memory difficulties (as anootropic), withdrawal symptoms, alcohol- and/or drug- and/or medicinesabuse and/or dependency, sexual dysfunction, cardiovascular diseases,hypotension, hypertension, tinnitus, pruritus, migraine, hearingdifficulties, deficient intestinal motility, impaired nutrientabsorption, anorexia, obesity, locomotive disorders, diarrhoea,cachexia, urinary incontinence or as a muscle relaxant, anti-convulsiveor anaesthetic for co-administration in treatment with an opioidanalgesic or anaesthetic, for diuresis or anti-natriuresis, anxiolysis,for modulation of motor activity, for modulation of neurotransmitterrelease and treatment of neurodegenerative diseases associatedtherewith, for the treatment of withdrawal symptoms and/or for reducingthe potential for addiction to opioids.

In one of the above uses it may be preferred if a substitutedcyclohexylcarboxylic acid derivative used is present as a purediastereomer and/or enantiomer, as a racemate or as non-equimolar orequimolar mixture of diastereomers and/or enantiomers.

The invention also relates to a process for the treatment, in particularin one of the above-mentioned indications, of a non-human mammal or ahuman, which or who requires treatment of pain, in particular chronicpain, by administration of a therapeutically effective dose of asubstituted cyclohexylcarboxylic acid derivative according to theinvention, or of a pharmaceutical composition according to theinvention.

The invention also relates to a process for producing the substitutedcyclohexylcarboxylic acid derivatives according to the invention asstated in the following description and examples.General Synthesis Pattern

R⁰¹ and R¹⁰² have the meaning of R¹ and R² and can additionally assumethe meaning of a protecting group.

The production of suitable 4-aminocyclohexanones according to formula Ais known from the literature (Lednicer et al., J. Med. Chem. 23, 1980,424-430; WO 0290317).

An alkoxymethyl-phosphonium salt, preferably methoxymethyl-triphenylphosphonium chloride or methoxymethyltriphenylphosphonium bromide, isfirstly reacted with a strong base, preferably potassium-tert.butylate,sodium hydride or butyllithium, and then with a 4-aminocyclohexanoneaccording to formula A. A cyclohexylcarbaldehyde according to formula IIis produced.

The cyclohexylcarbaldehyde II is oxidized with a suitable oxidizingagent, preferably with potassium permanganate, chromium(VI)oxide orother chromium(VI)-salts, to form corresponding cyclohexylcarboxylicacid according to formula III.

The carboxylic acid according to formula III as such or as itscorresponding hydrochloride is reacted with a dehydrating reagent,preferably with a carbodiimide, more preferably withdicyclohexyl-carbodiimide, in the presence of an activation reagent,preferably with 1-hydroxybenzotriazole, with an amine of formula R⁴R⁵NHto form the corresponding amide according to formula I.

The protecting groups at R⁰¹ and R⁰² are optionally subsequently cleavedby methods known to a person skilled in the art.Alternative Method of Synthesis:

A cyclohexane-1,4-dione according to formula B, protected by the groupsS¹ and S², which represent protecting groups—for example substituted orunsubstituted alkyl, in particular (CH₂)_(n) where n=2-4, is reacted inthe presence of a strong base, preferably potassium-tert.butylate,sodium hydride or butyllithium, with an alkoxymethyl-phosphonium salt,preferably methoxymethyl-triphenyl-phosphonium chloride ormethoxymethyl-triphenylphosphonium bromide. A cyclohexylcarbaldehydeaccording to formula IV is produced.

The cyclohexylcarbaldehyde IV is oxidized with a suitable oxidizingagent, preferably with potassium permanganate, chromium(VI)oxide orother chromium(VI)-salts, to form the corresponding cyclohexylcarboxylicacid. This carboxylic acid is reacted as such or as its correspondinghydrochloride with a dehydrating reagent, preferably with acarbodiimide, more preferably with dicyclohexyl-carbodiimide, in thepresence of an activation reagent, preferably with 1-hydroxybenzotriazole, with an amine of formula R⁴R⁵NH to form the correspondingamide according to formula V.

The protecting groups S¹ and S² are cleaved from the compound accordingto formula V, to form a 4-substituted cyclohexanone derivative accordingto formula VI.

The compound according to formula VI is reacted in the presence of acompound of formula HNR⁰¹R0² with a cyanide, preferably potassiumcyanide or TMSCN, to form a 4-substituted 1-amino-1-cyano-cyclohexanederivative according to formula VII.

The aminonitrile according to formula VII is reacted with organometallicreagents, preferably Grignard or organolithium reagents, of the formulametal-R³, to form the compounds according to the invention according toformula I.

The protecting groups at R⁰¹ and R⁰² are optionally subsequently cleavedby methods known to a person skilled in the art.

EXAMPLES

The following examples are intended to describe the invention in furtherdetail without limiting the scope of the invention. The yields ofcompounds produced have not been optimized. All temperatures areuncorrected.

As used herein, the term “ether” denotes diethylether, “THF”tetrahydrofuran, “DMF” dimethylformamide, “EE” ethylacetate and “DCM”dichloromethane. The term “equivalent” denotes amount of substanceequivalent, “mp” melting point or melting range, “decomp.”decomposition, “RT” room temperature, “abs.” absolute (anhydrous),“rac.”racemic, “conc.” concentrated, “min” minutes, “h” hours, “d” days, “vol.%” volume percent, “m %” mass percent and “M” is a concentration inmol/l.

Silica gel 60 (0.040-0.063 mm) from E. Merck, Darmstadt was used as thestationary phase for column chromatography. The thin-layerchromatography tests were carried out using HPTLC chromatoplates, silicagel 60 F 254, from E. Merck, Darmstadt. The mixing ratios of eluants forchromatographic tests are always given in volume/volume.

The compounds used in the following examples were either commerciallyavailable, or production thereof is known in the art or has been derivedfrom the prior art in a manner obvious to persons skilled in the art.

4-dimethylamino-4-phenyl-cyclohexanecarbaldehyde

46 mmol (10.0 g) of 4-dimethylamino-4-phenylcyclohexanone were dissolvedin toluene. This solution was added dropwise at 70° C. to a suspensionof 138.1 mmol, (47.33 g) methoxymethyl triphenylphosphonium chloride and138.1 mmol (25.82 g) potassium tert.-butylate. The mixture was stirredfor a few more hours at 70° C., hydrolysed with water and extractedusing EE. The combined organic phases were washed with saturated NaClsolution, dried over sodium sulphate and concentrated. The resultantbrown resin was chromatographed using silica gel. The desired aldehydeis obtained as a cis/trans-mixture.

4-dimethylamino-4-phenyl-cyclohexanecarboxylic acid hydrochloride

4-dimethylamino-4-phenyl-cyclohexanecarbaldehyde (2,3 g, 10 mmol) wasdissolved in THF (60 ml). Potassium permanganate (3 g, 19 mmol) wasdissolved in 50 ml distilled water at 50° C., cooled to RT and addeddropwise to the solution of the aldehyde, so the temperature was keptbelow 40° C. The mixture was stirred for 3 h at RT. Precipitatedmanganese dioxide was suction-filtered and washed thoroughly with THFand water in succession. The combined filtrates were evaporated andextracted with ether (3×15 ml). The pH was then adjusted to 1 using 2Mhydrochloric acid and the mixture was shaken out again with ether (3×20ml). The aqueous phase was evaporated to dryness. The residue was driedover P₂O₅. The solid was suspended in isopropanol (30 ml), the insolubleresidue suction-filtered, the mother liquor evaporated and mixed withether until cloudy. After cooling for 16 hours the resultant precipitatewas suction-filtered, washed with ether and dried. 1.5 g (54%) of4-dimethylamino-4-phenyl-cyclohexanecarboxylic acid hydrochloride withan mp of 112-130° C. were obtained by fractional precipitation.

2-[(4-dimethylamino-4-phenyl-cyclohexanecarbonyl)-amino]-3-(1H-indol-3-yl)-propionic acid-methylester-hydrochloride(Examples 1 and 2)

4-dimethylamino-4-phenyl-cyclohexanecarboxylic acid hydrochloride (568mg, 2 mmol) and L-tryptophan-methylester-hydrochloride (509 mg, 2 mmol)were dissolved in 5 ml dry DMF and N-methylmorpholine (0.88 ml, 8 mmol)was added. After 10 minutes 1-hydroxybenzotriazole (1 g, 8 mmol) wasadded, the mixture cooled to 0° C. and dicyclohexylcarbodiimide (1.6 g,8 mmol) introduced. For working up, the precipitate was suction-filteredand washed with cold DMF. The filtrate was added to a mixture ofsaturated NaCl-solution (93 ml) and saturated sodium hydrogen carbonatesolution (7 ml). Ether was added, the phases were separated, the etherphase was dried and concentrated. A portion of the non-polardiastereoisomer (25 mg, 2.8%) was isolated from the residue (1.3 g) bychromatography. The aqueous phase was extracted with EE, adjusted to pH10 with 1M NaOH and shaken out again with EE. The combined organicphases were dried and concentrated. The non-polar diastereoisomer (14mg, 1.5%), the polar diastereoisomer (62 mg, 7%) and a mixed fraction(75 mg, 8.4%) were isolated from the residue (862 mg) by chromatography.

The non-polar diastereoisomer (72 mg, 0.16 mmol) was dissolved inethanol (20 ml). 3.3 M ethanolic HCl (75 μl, 0.24 mmol) was added at RTand the mixture was stirred for 2 h. The solvent was distilled off andthe residue ground with ether. The resultant solid was suction-filteredand washed with ether. The non-polar diastereoisomer of2-[(4-dimethylamino-4-phenyl-cyclohexanecarbonyl)-amino]-3-(1H-indol-3-yl)-propionicacid methylester-hydrochloride was thus obtained as a beige solid (70.2mg, 91%) with an mp of 138-144° C. (Example 1).

The process was carried out in a similar manner with the polardiastereoisomer (77 mg, 0.17 mmol). The hydrochloride of the polardiastereoisomer was thus obtained as a beige solid (83 mg, 99%) with anmp of 185-195° C. (Example 2).

4-dimethylamino-4-phenyl-cyclohexane carboxylic acid(3-phenyl-propyl)-amide hydrochloride (Examples 3 and 4)

4-dimethylamino-4-phenyl-cyclohexanecarboxylic acid hydrochloride (357mg, 1.25 mmol) and 3-phenyl-propylamine-hydrochloride (170.1 mg, 1.25mmol) were dissolved in dry DMF (6 ml) and N-methylmorpholine (0.28 ml,2.5 mmol) was added. After 10 minutes 1-hydroxybenzotriazole (510 mg,3.8 mmol) was added, the mixture cooled to 0° C.,dicyclohexylcarbodiimide (778 mg, 3.8 mmol) introduced and stirred for 6days at RT. For working up, the reaction mixture was cooled for 2 h, thesolid suction-filtered and washed with cold DMF. A cooled mixture ofsaturated NaCl solution (46 ml) and saturated sodium hydrogen carbonatesolution (4 ml) was added to the filtrate. Ether was added and thephases were separated. The ether phase was dried and concentrated. Theaqueous phase was extracted with dichloromethane (4×10 ml). Thedichloromethane extracts were dried and concentrated. The extractionresidues were combined and purified by chromatography. The non-polardiastereoisomer (21 mg, 4%), a mixture (30 mg, 7%) and the polardiastereoisomer (109 mg, 24%) were obtained.

The non-polar diastereoisomer (20 mg, 0.05 mmol) was dissolved inethanol (2 ml) and methylethylketone (2 ml). 3.3 M ethanolic HCl (25 μl,0.08 mmol) was added at RT and stirred for 2 h. The solvent wasdistilled off and the residue ground with ether. The resultant solid wassuction-filtered and washed with ether (2×1 ml). The non-polardiastereoisomer of 4-dimethylamino-4-phenyl-cyclohexanecarboxylic acid(3-phenyl-propyl)-amide hydrochloride was thus obtained as a lightyellow solid (19 mg, 88%) with an mp of 100-105° C. (Example 3).

The process was carried out in a similar manner with the polardiastereomer (105 mg, 0.29 mmol). The hydrochloride of the polardiastereomer was thus obtained as a colorless solid (115 mg, 96%) withan mp of 112-115° C. (Example 4).

Tests of the Efficacy of the Comounds of the Invention

Measurement of ORL1 Binding

The cyclohexane derivatives of general formula I were investigated in areceptor binding assay using ³H-nociceptin/orphanin FQ with membranes ofrecombinant CHO-ORL1 cells. This test system was carried out by themethod presented by Ardati et al. (Mol. Pharmacol. 51, 1997, pp.816-824). The concentration of ³H-nociceptin/orphanin FQ was 0.5 nM inthese tests. The binding assays were each carried out with 20 μgmembrane protein per 200 μl batch 50 mM Hepes, pH 7.4, 10 mM MgCl₂ and 1mM EDTA. The binding with the ORL1 receptor was determined using 1 mgWGA-SPA beads (Amersham-Pharmacia, Freiburg), by incubation of the batchfor one hour at RT and subsequent measurement in the Triluxscintillation counter (Wallac, Finland). The affinity is shown in Table1 as a nanomolar K_(i) value in or % inhibition at c=1 μM.

Measurement of η-Binding

The receptor affinity for human μ-opiate receptor was determined in ahomogeneous batch in microtitre plates. For this purpose, dilutionseries of the respective substituted cyclohexylcarboxylic acidderivatives to be tested were incubated with a receptor membranepreparation (15-40 μg protein per 250 μl incubation batch) of CHO-KLcells, which express the human L-opiate receptor (RB-HOM receptormembrane preparation from NEN, Zaventem, Belgium) in the presence of 1nmol/l of the radioactive ligand [³H]-naloxone (NET719, NEN, Zaventem,Belgium) and 1 mg WGA-SPA beads (wheat germ agglutinin SPA beads fromAmersham/Pharmacia, Freiburg, Germany) in a total volume of 250 μl for90 minutes at room temperature. 50 mmol/l tris-HCl supplemented with0.05% by weight sodium azide and 0.06% by weight bovine serum albuminwere added as an incubation buffer. 25 μmol/l naloxone were also addedto determine the non-specific binding. At the end of the 90 minuteincubation period, the microtitre plates were centrifuged off for 20minutes at 1000 g and the radioactivity measured in a β-counter(Microbeta-Trilux, PerkinElmer Wallac, Freiburg, Germany). Thepercentage displacement of the radioactive ligand from its binding withthe human μ-opiate receptor at a concentration of the test substances of1 μmol/l was determined and given as a percentage inhibition (%inhibition) of the specific binding. IC₅₀ inhibition concentrations,which bring about a 50% displacement of the radioactive ligand, werepartially calculated by taking as a basis the percentage displacement byvarious concentrations of the compounds of general formula I to betested. K_(i) values for the test substances were obtained by conversionby means of the Cheng-Prusoff equation.

Measurement of Serotonin Re-Uptake

In order to carry out these in vitro studies, synaptosomes were freshlyisolated from rat brain areas. What is known as a “P₂” fraction was usedin each case. This was prepared in accordance with the instructionsprovided by Gray and Whittaker (E. G. Gray and V. P. Whittaker (1962) J.Anat. 76, 79-88). These vesicular particles were isolated from themedulla+pons region of male rats' brains for 5HT uptake. A detaileddescription of the method can be found in the literature (M.Ch. Frink,H.-H. Hennies, W. Englberger, M. Haurand and B. Wilfert (1996)Arzneim.-Forsch./Drug Res. 46 (III), 11, 1029-1036).

Measurement of Noradrenalin Re-Uptake

In order to carry out these in vitro studies, synaptosomes were freshlyisolated from areas of rats' brains. What is known as a “P₂” fractionwas used in each case. This was prepared in accordance with Gray andWhittaker's directions (E. G. Gray and V. P. Whittaker (1962) J. Anat.76, 79-88). These vesicular particles were isolated from thehypothalamus of male rats' brains for NA uptake. A detailed descriptionof the method can be found in the literature (M.Ch. Frink, H.-H.Hennies, W. Englberger, M. Haurand and B. Wilfert (1996)Arzneim.-Forsch./Drug Res. 46 (III), 11, 1029-1036).

The following binding data was determined, by way of example: ExampleNo. ORL1% [1 μM] 1 34.00 3 30.00

Example No. ORμnal % [1 μM] 1 55 2 34 3 70.5 4 59

5HT-uptake % inhibition Example No. [10 μM] 1 74 2 56 3 88 4 85

NA-uptake % inhibition Example No. [10 μM] 1 30 3 65 4 71Preparation of a Parenteral Solution of a SubstitutedCyclohexylcarboxylic Acid Compound According to the Invention

3.8 g of the compound of Example 1 were dissolved at room temperature in1 liter of water for injection purposes and then adjusted to isotonicconditions for injection purposes by adding anhydrous glucose.

This procedure for preparing a parenteral solution is fully applicableto the other substituted cyclohexylcarboxylic acid compounds accordingto the invention.

The foregoing description and examples have been set forth merely toillustrate the invention and are not intended to be limiting. Sincemodifications of the described embodiments incorporating the spirit andsubstance of the invention may occur to persons skilled in the art, theinvention should be construed broadly to include all variations withinthe scope of the appended claims and equivalents thereof.

1. A substituted cyclohexylcarboxylic acid amide compound correspondingto formula I:

wherein R¹ and R² independently represent H; CHO; respectively saturatedor unsaturated, branched or unbranched, singly or multiply substitutedor unsubstituted C₁₋₅ alkyl; respectively saturated or unsaturated,singly or multiply substituted or unsubstituted C₃₋₈ cycloalkyl; orrespectively singly or multiply substituted or unsubstituted aryl, C₃₋₈cycloalkyl or heteroaryl bound by C₁₋₃ alkyl; or R¹ and R² togetherrepresent CH₂CH₂OCH₂CH₂, CH₂CH₂NR¹⁰CH₂CH₂ or (CH₂)₃₋₆, wherein R¹⁰represents H; respectively saturated or unsaturated, branched orunbranched, singly or multiply substituted or unsubstituted C₁₋₅ alkyl;respectively saturated or unsaturated, singly or multiply substituted orunsubstituted C₃₋₈ cycloalkyl; respectively singly or multiplysubstituted aryl or heteroaryl; or respectively singly or multiplysubstituted or unsubstituted aryl, C₃₋₈ cycloalkyl or heteroaryl boundby C₁₋₃ alkyl; R³ represents respectively unsubstituted or singly ormultiply substituted cyclopentyl, cyclohexyl, naphthyl, thiophenyl,benzothiophenyl, furyl, benzofuranyl, benzodioxolanyl, indolyl, indanyl,benzodioxanyl or pyridyl; respectively unsubstituted or singly ormultiply substituted C₅₋₆ cycloalkyl, phenyl, naphthyl, anthracenyl,thiophenyl, benzothiophenyl, pyridyl, furyl, benzofuranyl,benzodioxolanyl, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyrimidyl orpyrazinyl bound by a saturated, unbranched C₁₋₂ alkyl group; phenyl,2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl,4-chlorophenyl, 3-chlorophenyl, 2-bromophenyl, 3-bromophenyl,4-bromophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl,2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl,3-methoxyphenyl, 4-methoxyphenyl, 2-trifluoromethylphenyl,3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-ethylphenyl,3-ethylphenyl, 4-ethylphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl,4-ethoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl,2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl,2,4-dichlorophenyl, 2,3-difluorophenyl, 3,4-difluorophenyl,3,5-difluorophenyl, 2,4-difluorophenyl, 2-fluoro-3-chlorophenyl,2-chloro-3-fluorophenyl, 2-chloro-4-fluorophenyl,2-fluoro-4-chlorophenyl, 4-fluoro-3-chlorophenyl,4-fluoro-3-methylphenyl, 4-tert.-butylphenyl, 4-fluoro-3-chlorophenyl,4-bromo-3-fluorophenyl, 3,5-bis(trifluoromethyl)phenyl,4-chloro-2-trifluoromethylphenyl, 2-methoxy-5-methylphenyl,5-chloro-2-methoxyphenyl, 4-phenoxyphenyl, 2-methylthiophenyl,3-methylthiophenyl, 4-methylthiophenyl, 5-fluoro-2-methoxyphenyl,4-chloro-3-trifluoromethyl or 4-bromo-2-methylphenyl; R⁴ represents—(CR⁶R⁷)_(n)R⁸, wherein n represents 0, 1, 2, 3, 4, 5 or 6, R⁶represents H or saturated or unsaturated, branched or unbranched,unsubstituted or singly or multiply substituted C₁₋₅ alkyl; R⁷represents H, saturated or unsaturated, branched or unbranched,unsubstituted or singly or multiply substituted C₁₋₅ alkyl, or COOR⁹,wherein R⁹ represents H or saturated or unsaturated, branched orunbranched, unsubstituted or singly or multiply substituted C₁₋₅ alkyl;or R⁶ and R⁷ form a ring (CH₂)_(k)CHR⁸(CH₂)_(m), where k=1, 2 or 3 andm=1 or 2, and R⁸ represents respectively unsubstituted or singly ormultiply substituted C₃₋₈ cycloalkyl, aryl or heteroaryl; and R⁵represents H or —(CH₂)₁R⁸, wherein 1 represents 1, 2 or 3, and R⁸ hasthe meaning given above, or R⁴ and R⁵ together with representCH₂CH₂OCH₂CH₂ or CH₂CH₂NR¹¹CH₂CH₂, wherein R¹¹ represents H;respectively saturated or unsaturated, branched or unbranched, singly ormultiply substituted or unsubstituted C₁₋₅ alkyl; respectively saturatedor unsaturated, singly or multiply substituted or unsubstituted C₃₋₈cycloalkyl; respectively singly or multiply substituted or unsubstitutedaryl or heteroaryl; or respectively singly or multiply substituted orunsubstituted aryl, C₃₋₈ cycloalkyl or heteroaryl bound by C₁₋₃ alkyl;in the form of a pure stereoisomer or a mixture of isomers in anyproportion, or a physiologically acceptable salt thereof.
 2. A compoundaccording to claim 1, wherein said compound in the form of a pureenantiomer or diastereomer.
 3. A compound according to claim 1, whereinsaid compound is in the form of a racemic mixture.
 4. A compoundaccording to claim 1, wherein R¹ and R² independently represent H;saturated or unsaturated, branched or unbranched, singly or multiplysubstituted or unsubstituted C₁₋₅ alkyl, or R¹ and R² together form aring and represent CH₂CH₂OCH₂CH₂, CH₂CH₂NR¹⁰CH₂CH₂ or (CH₂)₃₋₆, whereinR¹⁰ represents H; or saturated or unsaturated, branched or unbranched,singly or multiply substituted or unsubstituted C₁₋₅ alkyl.
 5. Acompound according to claim 4, wherein R¹ and R² independently representCH₃ or H, with the proviso that R¹ and R² do not simultaneouslyrepresent H.
 6. A compound according to claim 1, wherein R³ representsrespectively unsubstituted or singly or multiply substituted naphthyl,thiophenyl or pyridyl; respectively unsubstituted or singly or multiplysubstituted C₅₋₆ cycloalkyl, phenyl, naphthyl, thiophenyl, pyridyl boundby a saturated, unbranched C₁₋₂-alkyl group; phenyl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 4-chlorophenyl,3-chlorophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl,2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl,3-methoxyphenyl, 4-methoxyphenyl, 2-trifluoromethylphenyl,3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-ethylphenyl,3-ethylphenyl, 4-ethylphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl,4-ethoxyphenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl,3,5-dichlorophenyl, 2,4-dichlorophenyl, 2, 3-difluorophenyl,3,4-difluorophenyl, 3,5-difluorophenyl, 2,4-difluorophenyl,2-fluoro-3-chlorophenyl, 2-chloro-3-fluorophenyl,2-chloro-4-fluorophenyl, 2-fluoro-4-chlorophenyl,4-fluoro-3-chlorophenyl, 4-fluoro-3-methylphenyl, 4-tert.-butylphenyl,4-fluoro-3-chlorophenyl, 3,5-bis(trifluoromethyl)phenyl,4-chloro-2-trifluoromethylphenyl, 2-methoxy-5-methylphenyl,5-chloro-2-methoxyphenyl, 4-phenoxyphenyl, 2-methylthiophenyl,3-methylthiophenyl, 4-methylthiophenyl or 4-chloro-3-trifluoromethyl. 7.A compound according to claim 6, wherein R³ represents pyridyl, phenyl,3-fluorophenyl or 4-fluorophenyl.
 8. A compound according to claim 7,wherein R³ represents phenyl.
 9. A compound according to claim 1,wherein R⁶ represents H, and R⁷ represents H or COOR⁹.
 10. A compoundaccording to claim 1, wherein R⁵ represents H.
 11. A compound accordingto claim 1, wherein R⁸ represents respectively unsubstituted or singlyor multiply substituted cyclobutyl, cyclopropyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl,benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl,acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl,pyrazinyl or pyrimidyl, fluorenyl, fluoranthenyl, benzothiazolyl,benzotriazolyl or benzyl[1,2,5]thiazolyl or 1.2-dihydroacenaphtenyl,pyridinyl, furanyl, benzofuranyl, pyrazolinonyl, oxopyrazolinonyl,dioxolanyl, adamantyl, pyrimidinyl, quinolinyl, isoquinolinyl,phthalazinyl or quinazolinyl.
 12. A compound according to claim 11,wherein R⁸ represents respectively unsubstituted or singly or multiplysubstituted cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl,benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl,thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl or pyrimidyl.
 13. Acompound according to claim 12, wherein R⁸ represents respectivelysingly or multiply substituted phenyl or indolyl.
 14. A compoundaccording to claim 1, selected from the group consisting of:2-[(4-dimethylamino-4-phenyl-cyclohexanecarbonyl)-amino]-3-(1H-indol-3-yl)-propionic acid-methylester-hydrochloride;non-polar diastereomer;2-[(4-dimethylamino-4-phenyl-cyclohexanecarbonyl)-amino]-3-(1H-indol-3-yl)-propionicacid-methylester-hydrochloride; polar diastereomer;4-dimethylamino-4-phenyl-cyclohexanecarboxylic acid carboxylic acid(3-phenyl-propyl)amide hydrochloride; non-polar diastereomer, and4-dimethylamino-4-phenyl-cyclohexanecarboxylic acid(3-phenyl-propyl)-amide-hydrochloride; polar diastereomer, in the formof a pure stereoisomer or a mixture of isomers in any proportion, or aphysiologically acceptable salt thereof.
 15. A process for producing asubstituted cyclohexylcarboxylic acid amide compound according to claim1, said process comprising: reacting an alkoxymethyl-phosphonium salt inthe presence of a strong base with a 4-aminocyclohexanone; subsequentlyoxidizing with an oxidizing agent, and reacting with an amine of formulaR⁴R⁵NH in the presence of a dehydrating reagent and an activationreagent.
 16. A process according to claim 15, wherein said oxidizingagent is potassium permanganate, chromium(VI)oxide or a chromium(I)salt; said dehydrating agent is a carbodiimide; said activation reagentis 1-hydroxybenzotriazole, and said organometallic reagent is a Grignardor organolithium reagent.
 17. A process for producing a substitutedcyclohexylcarboxylic acid amide compound according to claim 1, saidprocess comprising: reacting a protected cyclohexane-1,4-dione in thepresence of a strong base with an alkoxymethyl phosphonium salt;oxidizing with an oxidizing agent; reacting with an amine of formulaR⁴R⁵NH in the presence of a dehydrating reagent and an activationreagent; cleaving the protecting group; reacting with a cyanide in thepresence of a compound of formula HNR⁰¹R⁰², and reacting with anorganometallic reagent of the formula metal-R³.
 18. A pharmaceuticalcomposition comprising a compound according to claim 1 and at least onepharmaceutical carrier or auxiliary.
 19. A method or treating paincomprising administering to a patient an effective pain alleviatingamount of a compound according to claim
 1. 20. A method according toclaim 19, wherein said pain is acute, visceral, neuropathic or chronicpain.
 21. A method of treating or inhibiting a condition selected fromthe group consisting of anxiety, stress and stress-related syndromes,depression, catalepsy, epilepsy, Alzheimer's disease, senile dementia,general cognitive dysfunction, learning and memory difficulties,withdrawal symptoms, alcohol, drug- and pharmaceutical abuse anddependency, sexual dysfunction, cardiovascular diseases, hypotension,hypertension, tinnitus, pruritus, migraine, hearing difficulties,deficient intestinal motility, impaired nutrient absorption, anorexia,obesity, locomotive disorders, diarrhoea, cachexia, and urinaryincontinence, or for muscle relaxant, anti-convulsive or anaesthetictreatment, or for co-administration in treatment with an opioidanalgesic or anaesthetic, or for diuresis or anti-natriuresis,anxiolysis, modulation of motor activity, modulation of neurotransmitterrelease and treatment of neurodegenerative diseases associatedtherewith, treatment of withdrawal symptoms, or for reducing thepotential for addiction to opioids, said method comprising administeringto a patient in need thereof a pharmaceutically effective amount of acompound according to claim 1.